KLK8 (kallikrein-related peptidase 8)

	The KLK8 gene comprises 8 exons (dark color, classic numerals) and 7 introns. Shown here are the 6 alternative transcripts predicted to encode protein variants (only the coding exons are depicted). Yellow boxes: non coding sequences; blue and green boxes: coding sequences. Sequences coding for identical amino acids are indicated in green whereas blue designates sequences generating distinct amino acids.
Description	The KLK8 gene is approximately 7.8 Kb in length, consisting of 8 exons (5 of them are coding exons) and 7 introns.
Transcription	Human KLK8 was originally cloned (Yoshida et al., 1998) as the human ortholog of the mouse brain protease neuropsin (Chen et al., 1995). Using Northern blot and RT-PCR analyses, it has been shown that KLK8 is expressed mainly in breast, cervix, esophagus, skin, ovary, testis, salivary glands and vagina. Adrenal, brain, colon, heart, kidney, lung, muscle and prostate also express KLK8 mRNA at medium to low levels. The transcription start site of KLK8 appears tissue-specific (Lu et al., 2009). Eight alternatively spliced variants have been identified for the KLK8 gene. These variants differ in the number and length of the 5' untranslated exons and/or coding exons. The splice variants are predicted to encode 6 protein isoforms. Type 1 and Type 2 transcripts differ in their coding exon 2 sequence. Type 2 includes extra 45 amino acids at the N-terminus of the coding exon 2. Thus, Type 1 and Type 2 KLK8 mRNA variants produce 2 zymogens that differ only in their propeptide sequences. Type 2 variant is absent in nonhuman primates, and is thus a human-specific splice form (Li et al., 2004; Lu et al., 2007). Type 1 mRNA is predominantly expressed in the pancreas and Type 2 mRNA in adult brain and hippocampus. Type 2 KLK8 is also abundantly expressed in fetal brain, placenta and in human embryonic stem cells, suggesting a potential role in embryogenesis (Mitsui et al., 1999; Lu et al., 2009). The Type 3 mRNA variant includes coding exons 1, 4, and 5 and encodes a truncated form of the KLK8 protein (Magklara et al., 2001). Type 4 variant lacks coding exons 2, 3, 4. It encodes a putative protein of 32 amino acid residues that contains the KLK8 signal peptide and another peptide that is not related to KLK8 (Magklara et al., 2001). Type 3 and Type 4 mRNAs are abundant in many normal tissues (brain, pancreas, skin) and are overproduced in ovarian and lung cancers (Magklara et al., 2001; Planque et al., 2010). Coding exon 2 is missing in Type 5 mRNA whereas Type 6 mRNA lacks coding exon 3. For these both variants, the alternative splicing creates a stop codon that prematurely terminates translation. Type 5 and Type 6 mRNAs were detected in lung cancer cell lines and tissues (Sher et al., 2006; Planque et al., 2010).
Pseudogene	None identified.

	Schematic structure of the KLK8 Type1 protein. The amino acid numbering for the residues of the catalytic triad (His70, Asp120, Ser212) are relative to the full-length protein starting from Met1.
Description	The canonical KLK8 protein encoded by Type 1 mRNA has a secretion signal (pre-) peptide (28 amino acids), followed by an activation (pro-) peptide (4 amino acids) and the mature chain (228 amino acids) with 1 potential N-linked glycosylation site. The catalytic triad of His73, Asp120, Ser212 (relative to Met = 1) is conserved and is essential for proteolytic activity. After synthesis as a KLK8 precursor, the signal peptide is then cleaved and pro-KLK8 (zymogen) is subsequently secreted from the cell. Upon activation, the propeptide is removed to generate the mature active enzyme. Type 2 KLK8 has an insert of 45 amino acids between Ala23 and Gly24 at the C-terminus of the leader sequence of canonical KLK8. Therefore, this isoform has larger signal peptide and propeptide and has been produced intact as recombinant protein (Lu et al., 2009). Beside the canonical KLK8 protein, only the predicted peptide encoded by KLK8 Type 4 mRNA has been yet detected in vivo. This form was identified by mass spectrometry in bronchoalveolar lavage fluid (Oumeraci et al., 2011).
Expression	KLK8 protein has been detected in a wide range of tissues at low (10 to 100 ng/g, adrenal, cervix, heart, kidney, liver, ovary, salivary gland, vagina) to high (1 µg to 10 µg/g, breast, esophagus, skin, tensil) levels (Shaw and Diamandis, 2007). KLK8 has also been detected in body fluid, such as milk, amniotic fluid, cerebrospinal fluid, seminal plasma, serum, saliva and sweat (Kishi et al., 2003; Shaw and Diamandis, 2007; Eissa et al., 2011). Age at the first full term pregnancy (FFTP) influences secretion of KLK8 protein in breast milk. Indeed in a recent study, a significant increase in KLK8 expression was observed from the onset of lactation to breast weaning depending on FFTP age (<26 or >26) (Qin et al., 2012).
Localisation	KLK8 is a secreted protein and is localized intracellularly to the cytoplasm. In epidermis, KLK8 is localized within the trans-Golgi network, lamellar granules and intercellular spaces between the stratum granulosum and stratum corneum (Ishida-Yamamoto et al., 2004). Diffuse cytoplasmic staining was observed for KLK8 in the secretory segment in eccrine sweat glands and in the intradermal sensory nerve (Komatsu et al., 2005). KLK8 is present in relatively high levels in ductal cells, as well as in non-ductal cells, of normal salivary gland tissues and benign and malignant salivary gland tumors (Darling et al., 2008). In brain, KLK8 is expressed in the cell body of oligodendrocytes (He et al., 2001).
Function	KLK8 is a serine protease which exhibits trypsin-like activity with strong preference for Arg over Lys in the P1 position (Kishi et al., 2006; Eissa et al., 2011). KLK8 activity is inhibited by general serine protease inhibitors such as a2-antiplasmin, protein C inhibitor and PI-6 (Proteinase inhibitor 6) (Scott et al., 2007). Several potential substrates have been identified for KLK8 in human or mouse including extracellular matrix components (Single-chain tPA, fibronectin, gelatin, collagen type IV, fibrinogen) (Rajapakse et al., 2005), cell adhesion molecules (L1cam) and membranous receptors (EphB2, PAR2) (Matsumoto-Miyai et al., 2003; Nakamura et al., 2006; Attwood et al., 2011; Ramachandran et al., 2012), antimicrobial peptides (LL-37) and zymogens of kallikrein-related peptidases (proKLK1 and proKLK11) (Eissa et al., 2011). The physiological functions of KLK8 are not fully understood. Accumulating evidence has suggested pivotal roles for KLK8 in development, maturation and cognitive functions. KLK8 induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity (Komai et al., 2000; Oka et al., 2002; Nakamura et al., 2006; Terayama et al., 2007; Horii et al., 2008; Yoshida, 2010; Ishikawa et al., 2011; Shiosaka and Ishikawa, 2011). KLK8 has also been involved in skin desquamation and wound healing and in keratinocyte proliferation (Inoue et al., 1998; Kirihara et al., 2003; Kishibe et al., 2007; Yoshida, 2010; Eissa et al., 2011; Kishibe et al., 2012). It has been shown that KLK8 is differentially expressed in a number of malignancies, including ovarian, cervical, head and neck, breast and salivary gland cancers (Kishi et al., 2003; Cane et al., 2004; Borgono et al., 2006; Darling et al., 2008; Liu et al., 2008; Kountourakis et al., 2009), but the mechanisms of its involvement in these cancer have yet to be determined. In lung cancer, KLK8 suppress tumor cell invasiveness in vitro and in vivo (Sher et al., 2006).
Homology	The human KLK8 protein sequence shares 40-70% homology with other members of the human tissue kallikreins, and 70% identity with that of the mouse orthologue.

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